Few studies of progression of atherosclerotic peripheral vascular disease (PVD) have been performed and none have used objective methods to evaluate disease progression in a large number of symptomatic subjects. The Homocysteine and Progression of Atherosclerosis Study (HPAS) is a long term prospective blinded multifactoral clinical study which began in 1991 to study the relationship between elevated plasma homocysteine (HC) as well as a number of other risk factors and PVD progression. The study is divided into two phases, conducted sequentially upon 400 patients with symptomatic lower extremity (LED) and cerebrovascular disease (CVD). The first phase is a three year natural history study in which relationship of progression of PVD to plasma HC and other risk factors is established. This study is currently funded and 2 and one half years in progress. The clinical question to be addressed by the natural history study is: Do patients with symptomatic PVD and elevated plasma HC have more rapid/frequent progression of PVD than patients with symptomatic PVD and normal plasma HC? Progression of disease is assessed by primary outcome variables of ankle brachial pressure index and degree of carotid artery stenosis, as determined in the noninvasive vascular laboratory, and by secondary outcome variables including vascular death, need for vascular surgery, stroke, myocardial infarction, amputation, and other clinical events. All outcome variables are determined by investigators blinded to the results of plasma HC testing. The natural history study has enrolled over 300 patients and the assumptions underlying the power calculations for the study have been validated by preliminary data. The initial patients will complete the study in late 1994. This proposal requests support for the second phase of HPAS, a blinded prospective randomized placebo controlled trial of folic acid treatment of plasma HC in the same patient population. Folic acid treatment has been demonstrated to result in normalization of elevated plasma HC. The treatment trial will address the clinical question: Do patients with symptomatic PVD and elevated plasma HC treated with folate have less frequent/rapid progression of PVD than patients with symptomatic PVD and elevated plasma HC treated with placebo? Completion of this study is of obvious major clinical importance. Elevated plasma HC is well established as an independent risk factor for atherosclerosis. If folate treatment results in less frequent/rapid progression of PVD, then it will be confirmed as the first effective treatment for atherosclerosis which is without toxic side effects and does not involve major changes in life/dietary habits. The HPAS study already underway is the only currently extant clinical research project with sufficient power and adequate multifactoral design to objectively determine the role of treatment of elevated plasma HC on PVD progression.